Alnylam Pharmaceuticals Inc (ALNY) 2018 Q1 法說會逐字稿

Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals Conference Call to Discuss First Quarter 2018 Financial Results. (Operator Instructions) Please be advised that this call is being taped at the company's request.

I would now like to turn the call over to the company.

Good afternoon. I'm Christine Lindenboom, Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are John Maraganore, Chief Executive Officer; Barry Greene, President; Akshay Vaishnaw, President of R&D; Manmeet Soni, Chief Financial Officer; and Yvonne Greenstreet, Executive Vice President and Chief Operating Officer.

For those of you joining via conference call, the slides we have made available via webcast can also be accessed by going to the Investor page of our website, www.alnylam.com.

During today's call, as outlined on Slide 2, John will provide some introductory remarks and provide some general context; Akshay will review our R&D process; Manmeet will review our financials; Barry will provide an update of our commercial readiness efforts and Yvonne will provide a brief summary of upcoming milestones before opening the call for your questions.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recently annual report on file with the SEC.

The press release and related financial tables including a reconciliation of GAAP to non-GAAP measures that we will discuss today can also be found on the Investor page of our website. We believe non-GAAP measures provide a useful information to investors regarding our financial condition and results of our operation.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements.

With that, I will now turn the call over to John.

Thanks, Christine, and thank you, everyone, for joining the call today. The first quarter of 2018 was an exciting time as Alnylam continued its transition toward a commercial stage company and toward achievement of our Alnylam 2020 goals. We are at the cusp of bringing patisiran to the market with approvals anticipated in the U.S. in mid-2018 and in the EU in late 2018.

With today's announcement of having enrolled our 30th patient in ENVISION, we are now positioned to have top line Phase III interim analysis results with givosiran in the September time frame, with a potential NDA filing at or around year-end assuming positive results.

And now we believe today's update on our lumasiran program will significantly accelerate our time line for bringing yet another potential breakthrough medicine to patients with the Phase III start moved up to mid-2018 and top line data expected in 2019, which if positive, could enable an NDA in early 2020.

In addition, we remain on track to start another Phase III later this year for ALN-TTRsc02, a once-quarterly subcutaneous treatment option for all forms of ATTR amyloidosis with the potential to significantly expand our opportunity across all patient groups.

Akshay will go into these important development milestones in just a minute and Barry will discuss our commercialization efforts shortly thereafter. So let's take a step back to reflect on how Alnylam is now positioned for the future.

As a company, we expect to have launches of 4 potentially transformative medicines, 3 of which are designated breakthrough therapies by the FDA on an annual basis between 2018 and 2021. We have global rights for all of these programs and intend to commercialize them directly in North America, Europe, Japan and other significant markets around the world, creating a steady flow of Phase III data readouts, regulatory submissions, potential product approvals and the opportunity for significant revenue growth over this period and beyond.

At the same time, our partner, The Medicines Company, has fully enrolled its Phase III ORIONs 9, 10 and 11 trials of inclisiran with over 3,500 patients and data expected at 2019. And our partner, Sanofi, is advancing patisiran in the ATLAS Phase III trials with the goal of expanding its newly acquired leadership position in hemophilia, a $10 billion market. In both cases, Alnylam stands to benefit with significant royalties that approximate profit share levels. And with our product engine capable of yielding 2 to 3 new INDs per year, and possibly more, we believe we have a pipeline to continue to deliver sustainable growth from 2021 and beyond. In short, we believe the next 3 to 4 years are truly going to be remarkable for Alnylam's evolution, growth and value creation.

Of course, what matters the most is the difference we can make in patients' lives, and as we advance patisiran, givosiran and lumasiran and then ALN-TTRsc02 towards the market, we're very excited about the potential impact we can have for patients, their families and their caregivers.

So with that, let me turn the call over to Akshay to review our recent R&D highlights. Akshay, take it away.

Thanks, John, and good afternoon, everyone. Let's begin with patisiran, which is in development for the treatment of hereditary ATTR amyloidosis. Patisiran is currently under regulatory review by the FDA and EMA, and we continue to work collaboratively with both agencies through the patisiran review process with the goal of making this medicine available to patients as quickly as possible upon approval.

As you know, last fall, we presented results from the APOLLO Phase III study of patisiran. In APOLLO, patisiran demonstrated the potential to improve disease manifestations in a majority of patients with the negative change at 18 months in the mNIS+7 primary endpoint, and the Norfolk-QOL, key secondary endpoint compared to baseline. Patisiran is the only investigational or approved therapy to have demonstrated a potential improvement in hATTR amyloidosis disease manifestations in the majority of patients in the clinical study. Furthermore, patisiran was associated with an encouraging safety profile. APOLLO is the largest clinical study of patients with hATTR amyloidosis conducted today, and we continue to gather and analyze new data to describe the diverse aspects of patisiran's efficacy and safety.

In this regard, we were pleased to present new data just last week at the AAN conference from a post-hoc analysis of APOLLO data looking at the impact of patisiran treatment on hospitalization and mortality. In the figures on Slide 8, mortality and hospitalization events depicted over 18 months. The figure on the left depicts composite rate of all-cause hospitalization and mortality. As you can see, there's an approximately 50% decrease in this rate over 18 months in patisiran treated patients relative to placebo. Similarly, in the figure on the right, we observed an approximately 45% reduction in the composite rate of cardiac hospitalization and all-cause mortality in patients treated -- in patisiran-treated patients relative to placebo. We believe these post-hoc data strengthen the existing body of evidence demonstrating that patisiran, if approved, has the potential to be a transformative treatment for patients with all forms of hereditary ATTR amyloidosis.

As you may recall, with regards to safety and tolerability in the APOLLO study, there were 13 deaths overall, none of which were considered related to study drug, and the frequency of deaths was lower in the patisiran group as compared to placebo. Adverse events leading to treatment discontinuation were lower in the patisiran group as compared to placebo. The most commonly reported adverse events that occurred more frequently in patisiran-treated patients were peripheral edema and infusion-related reactions. These were generally mild to moderate in severity.

We also recently presented additional data at the ISA meeting in March. It included results from the cardiac subpopulation, highlighting that patisiran treatment was associated with improvements in multiple measures of cardiomyopathy. These improvements, in conjunction with demonstrated benefits in neurologic improvement appears to be associated with favorable effects on gait speed, an important indicator of functional status. Furthermore, improvements across a range of echocardiographic parameters, including left ventricular wall thickness and left ventricular strain as well as a positive effect on levels of NT-proBNP, a cardiac stress biomarker, also speak to the potential for significant benefits of patisiran for patients with hATTR amyloidosis with cardiac involvement.

We believe we're on track for a mid-2018 approval in the U.S., with an August 11 PDUFA date, and a late-2018 approval in the EU, where our application is being reviewed under an accelerated assessment. We also plan to submit our JNDA in Japan in mid-2018 as well as other regulatory packages in additional rest of the world countries later in the year.

In addition to patisiran, we're also developing ALN-TTRsc02 as an investigational RNAi therapeutic for ATTR amyloidosis. TTRsc02 uses our ESC-GalNAc-conjugate platform technology and allows for subcutaneous administration. In the Phase I study, single doses of TTRsc02 demonstrates a robust TTR knockdown that was maintained for over 300 days and supported the potential for low dose of 25 milligrams given as a once-quarterly subcutaneous injection to achieve levels of TTR knockdown comparable to those observed with patisiran in the APOLLO study.

TTRsc02 is generally well tolerated with no SAEs or study discontinuations due to AEs. Consistent with our previous guidance, we expect to advance ALN-TTRsc02 into a comprehensive pivotal Phase III program in late 2018. While our final trial is under pending FDA and EMA alignment, we believe the study with TTR knockdown as an endpoint would support an approval of TTRsc02 in the hATTR amyloidosis population bringing a very attractive subcutaneously administrated treatment options to patients as rapidly as possible.

Regarding the wild-type ATTR opportunity, we'll need to see the complete results from Pfizer's ATTR-ACT study with tafamidis later this year, but we're now considering the potential for a head-to-head study comparing TTRsc02 with tafamidis in affecting of ATTR cardiomyopathy, including wild-type disease.

Let's now turn to our givosiran program where we've also made significant progress in recent months. As you know, givosiran is in development for the treatment of acute hepatic porphyrias. At EASL last month, we presented complete data from all 4 dose cohorts in Part C of the Phase I trial as well as data from the ongoing OLE study. In Part C of the Phase I study, givosiran administration resulted in reductions in both aminolevulinic acid, or ALA, the primary neurotoxic intermediate responsible for disease manifestations and porphobilinogen, or PBG, another disease biomarker. Moreover, givosiran administration led to mean reductions in the annualized attack rate of 83% and in the annualized hemin consumption of 88% relative to placebo. The vast majority of the Part C patients rolled over into the OLE study and have now received givosiran treatment for up to 22 months with a mean treatment duration of about 11 months.

With extended dosing there was evidence for further improvement of clinical activity as patients transitioned from the Phase I into the Phase I/II OLE, specifically, we observed mean reductions in AAR of 93% and annualized hemin use of 94% relative to the attack rate and hemin use recorded for the Phase I running period. These reductions in AAR and hemin use exceeded those observed in the treatment period during Phase I, suggesting that continued givosiran dosing can generate even further amelioration of disease symptoms.

In terms of safety, 6 patients presented serious adverse events in the Phase I study with none of that was related to study drug. In the OLE study, 2 patients had SAEs. 1 SAE assessed to be definitely related to givosiran occurred in a patient who had anaphylactic reaction after receiving the third dose of givosiran. The patient had a past history of asthma or allergy syndrome and allergic reactions to acne cream and possibly latex gloves. The event resolved with medical management and the patient subsequently discontinued from the study. Furthermore, there were no antidrug antibodies, including IgE detected in this patient. Notably, this case represents the only report of an anaphylactic reaction that we have seen in over 2,500 patients dosed with GalNAc-conjugate of sRNAs across our entire pipeline, giving us reassurance that this is an isolated event.

We also plan today -- we also announced today in our earnings release that we've enrolled the first 30 patients in the ENVISION Phase III study of givosiran. These patients comprise the cohort in which we will report results from an interim analysis when they reach 3 months of dosing. This interim analysis will evaluate reductions in the levels of urinary ALA as a surrogate endpoint, but it's reasonably likely to predict clinical benefit. If the interim analysis is positive and pending regulatory support, we'll then be in a position to file an NDA for an accelerated approval based upon the interim study result at/or around year-end 2018, representing a significant acceleration in our efforts to bring this promising investigational medicine to patients.

We've also announced in our earnings release that we've had positive discussions with European regulators regarding the path forward of givosiran. Also in the path forward for conditional marketing authorization under an accelerated pathway, market access considerations lead us to believe that the best path forward in Europe is to wait for the full ENVISION's trial results in 2019 and then submit the MAA with full results assuming they're positive.

Let's turn now to recent progress of lumasiran, which is in development for the treatment of primary hyperoxaluria type 1 or PH1. As a reminder, PH1 is an ultra rare orphan disease, primarily in children in which oxide crystals build up in kidney leading to painful and recurrent kidney stones and damage to kidney and other tissues. Treatment options are limited and typically involve chronic dialysis and often a dual liver-kidney transplant. Lumasiran targets the enzyme glycolate oxidase, thereby depleting substrate necessary for the production of oxalate, which directly contributes to the pathophysiology of PH1.

We were very pleased recently to announce that we have retained global rights to lumasiran following the decision by Sanofi to decline its opt-in for lumasiran's development and commercialization. We have now completed enrollment in the Phase I/II study with 20 PH1 patients. We expect to report additional clinical results later this year. These patients are now beginning to roll over into a Phase I/II OLE study, which will evaluate the long-term safety and efficacy of lumasiran in PH1 patients. Based on our promising Phase I/II data, we're pleased to receive breakthrough designation in the U.S. and PRIME designation in the EU.

Just this morning, we announced that we reached alignment with the FDA on the design of our pivotal trial for lumasiran. Specifically, the pivotal trial will have a primary endpoint based on reduction of urinary oxalate at 6 months. The study will have a sample size of approximately 25 patients. Based on this new design, we now expect to start Phase III study in mid-2018, earlier than our previous guidance of late 2018, and to report top line results from this trial in 2019. Assuming positive results, we expect to be in a position to submit an NDA in early 2020, which represents a significant acceleration in our efforts to bring this investigational medicine to patients.

Let's turn briefly to our partnered programs, and I'll begin with our fitusiran program, which is in development for the treatment of hemophilia and rare bleeding disorders. Our Phase II OLE study is back up and running, and in the first quarter, we were pleased together with our partners at Sanofi to initiate dosing in the ATLAS Phase III program.

Turning to inclisiran for the treatment of hypercholesterolemia. We've been very impressed with the execution by our partner The Medicines Company, having fully enrolled the ORION-9, -10 and -11 studies with 3,660 patients. Here too, we look forward to seeing top line results from the Phase III program in 2019. Importantly, these studies comprised the largest safety database for GalNAc assigned conjugate, and we look forward to further safety updates going forward, which so far have been encouraging. As of now, the inclisiran studies have provided us with over 1,000 patient years of exposure, and every day adds another 5 years of safety data. The Medicines Company is also planning to conduct a cardiovascular outcomes trial ORION-4, which is expected to enroll 15,000 patients and begin in mid-2018.

Finally, we're also excited about our next wave of clinical programs. We've guided to have at least one new CTA in 2018, and we're on track to achieve or exceed this goal, which also include the advancement of our ESC+ platform programs beginning with our ALN-AAT02 program alpha-1 antitrypsin deficiency, associated liver disease and ALN-HBV02 with our partner, Vir.

In summary, we had a very exciting first quarter of 2018, and in the recent period, having now advanced the pipeline with 4 programs in Phase III with one on the regulatory review and multiple earlier-stage programs.

With that, I'll now turn it over to Manmeet to review our financial results. Manmeet?

Thanks, Akshay, and good afternoon. Please refer to our press release issued earlier today for a summary of financial results for the first quarter of 2018. I would like to take this opportunity to provide a brief overview of 3 key areas: Our cash position, our first quarter results and our updated 2018 financial guidance.

So turning to Slide 19, let me start with our cash balance. We maintained a strong balance sheet, ending the first quarter of 2018 with approximately $1.6 billion in cash, cash equivalents, fixed income marketable securities and restricted investments.

Moving to our financial results for the first quarter. We recognized $21.9 million of collaboration revenue during the first quarter of 2018 as compared to $19 million during the first quarter of 2017. The amount recognized during the first quarter of 2018 relates primarily to the achievement of $50 million milestone payment due from Sanofi Genzyme upon dosing of the first patient in the ATLAS Phase III program for fitusiran recognized using the proportionate performance method based on the new revenue recognition standard.

As a result of our adoption on January 1 of the new revenue recognition standard, we recognized significantly lower revenues during the quarter from our alliance with Sanofi Genzyme. To compare under the previously applicable revenue recognition guidance, we would have recognized approximately $33 million more in revenue during the first quarter.

Moving to expenses. Our GAAP R&D expenses were $96.9 million in the first quarter of 2018 as compared to $87 million in the first quarter of 2017. Non-GAAP R&D expenses were $86.7 million in the first quarter of 2018 as compared to $78.3 million in the first quarter of 2017. The increase in R&D expense was due primarily to increased compensation and related expenses as a result of an increase in headcount during the period as we expand and advance our development pipeline. Non-GAAP R&D expenses excludes stock-based compensation expense.

Our GAAP G&A expenses were $72.4 million in the first quarter of 2018 as compared to $38.5 million in the first quarter of 2017.

Non-GAAP G&A expenses were $63 million in the first quarter of 2018 as compared to $31.5 million in the first quarter of 2017. The increase in G&A expenses was due primarily to an increase in commercial and medical affairs headcount and commercial-related services to support corporate growth and prepare for the potential launch of patisiran in 2018 and potential additional product launches in 2019 and thereafter. Non-GAAP G&A expenses also excludes stock-based compensation expense.

With respect to guidance for 2018, we remain on track to end 2018 with approximately $1 billion in cash, cash equivalents and fixed income marketable securities, restricted cash and restricted investments. We believe this will provide Alnylam with a very strong balance sheet at the end of 2018 to support continued development and commercial activities.

As you may have noted in the press release issued today, we updated our 2018 annual non-GAAP R&D expense guidance to be in the range of $420 million to $460 million as compared to our previous guidance range of $400 million to $440 million. This increase of $20 million in the non-GAAP R&D expense guidance range reflects additional expenses expected due to the inclusion of the lumasiran program in our ongoing program portfolio. We are also reaffirming our 2018 annual non-GAAP SG&A expense guidance to be in the range of $280 million to $320 million.

With that, I will now turn the call over to Barry. Barry?

Thanks, Manmeet. As you heard from John and Akshay, we've made remarkable strides in the first quarter and recent period. Let me first provide some comments on our commercial preparation for patisiran. As of now, we believe we're launch-ready in the United States. Our U.S. field team is on board and we're in a position to get patisiran to patients as soon as possible once the drug is approved. We'll also soon be launch-ready in Europe. We've begun to hire and on board our field and customer-facing team in our earliest launch countries.

Outside of the U.S. and Europe, we also plan to have an Alnylam presence in Japan later this year. As you're aware, a key challenge in hereditary ATTR amyloidosis, as in many orphan diseases, is raising awareness and improving patient identification. The opportunity to find more patients is dramatic. The field is finding new pathogenic mutations annually. With the emergence of 3 companies actively educating in this disease, we feel confident that we can make significant inroads on awareness and in shortening the diagnostic process.

To do so, we must acknowledge the challenges we've seen in the patients journey to diagnose and develop ways to address them. As we speak with patient groups, they report that many patient journeys take longer than 2 years and some have reported over a decade of misdiagnosis and hospitalizations.

Alnylam has been working diligently to improve diagnosis through a number of initiatives. For example, we have a program called Alnylam Act, a free third-party genetic testing service in the U.S. and Canada. At the AAN meeting last week, we provided an update on the success of Alnylam Act, where approximately 4,600 samples have now been tested, which has led to the identification of TTR mutations in about 350 patients.

Among other efforts, we're also pleased to have an active Expanded Access Program in the U.S. in Europe, providing early access to patisiran in response to requests from treating physicians for eligible patients. As we announced in our press release, we've now fulfilled physician requests for more than 150 patients who have been dosed with patisiran in the U.S. and certain European countries. We believe this is indicative of the unmet need in hATTR amyloidosis and a measure of the increased disease awareness among health care professionals and patients and their families.

It seems that we're now seeing a new beginning where in certain instances, patients are coming forward to seek help with greater knowledge of their potential disease. Aided by genetic testing and counseling and the hope of treatment, some diagnosed patients are also starting to come forward to help other family members seek diagnosis. While most have not historically pursued testing for their families, we're getting to see the very beginning of a trend in this direction. And certainly, this is a transformative time for patients with hATTR amyloidosis. We're incredibly excited as we plan to launch the first-ever commercial launch of an RNAi therapeutic, and we're on track with launch readiness as I mentioned before.

Just like the steps we've taken to prepare for patisiran's commercial advancement, we're now taking similar activities for givosiran. For example, we recently expanded Alnylam Act to include testing and counseling for individuals who may carry a gene mutation known to be associated with porphyria. To date, approximately 50 samples have been submitted by physicians for patients that exhibit symptoms consistent with porphyrias, out of which 8 have tested positive for known mutations associated with the disease. Furthermore, now that we have global rights to lumasiran, we're putting in place the capabilities to support PH1 community in raising disease awareness.

I'd also like to spend a moment to touch on the recent top line results regarding the Phase III ATTR-ACT study with tafamidis. We look forward to seeing complete results from this study, which we now expect in late August at the ESC conference in Munich. At a high level, a positive outcome from this study is very good for patients. Clearly, having more treatment options available serves to benefit patients, particularly it comes to a rare devastating fatal disease.

As we've discussed on this call and previous calls, the biggest challenge for hATTR amyloidosis is disease awareness and patient finding. Therefore, we believe that having other companies actively working to raise disease awareness, shorten the patient journey and improve patient diagnosis will result in an expansion of the overall market in a way that should ultimately increase the number significantly of patients diagnosed.

We see the hATTR amyloidosis disease setting as one that will benefit substantially more from market growth versus just market share. Similar to what's been seen before in other market settings like multiple sclerosis and HAE.

And of course, given the data from APOLLO in terms of primary and subsequent analysis, we remain confident that the patisiran product profile will be the best-in-class for patients, as patisiran is the only investigational or approved therapy that has been demonstrated to show improvements in disease manifestations in the majority of patients. And now we expect there'll be more patients and they will be identified sooner, leading to potentially greater benefit.

With that, I'll now turn the call over to Yvonne to review our mid-2018 goals. Yvonne?

Thanks, Barry. I'll be referring to Slide 24 to review our mid-2018 goals.

In 2018, most importantly, we expect the transition to commercial phase company with U.S. approval and launch of patisiran anticipated in mid-2018 and EMA approval and launch in the EU anticipated in late 2018. We will also start our global efforts on patisiran with the JNDA filing expected in mid-2018 and additional Rest-of-World regulatory submissions by year-end.

In the September time frame, we expect to report top line interim analysis from the ENVISION Phase III study of givosiran for acute hepatic porphyrias leading to a potential year-end NDA submission. And as we announced this morning, we also expect to start our lumasiran Phase III study in mid-2018.

Also, we'll be advancing our additional Phase III programs together with our partners. With fitusiran, we and Sanofi expect to enroll patients in the ATLAS Phase III program throughout the course of this year. And we'll also continue to support The Medicines Company as they execute on the ORION Phase III program, and they have also guided their intention to kick off a cardiovascular outcome study called ORION-4 in mid-2018.

With that, I will now turn the call back to Christine to coordinate our Q&A. Christine?

Thanks, Yvonne. Operator, we'll now open the call for your questions. (Operator Instructions)

(Operator Instructions) And our first question comes from the line of Alethia Young with Crédit Suisse.

This is Ellie on for Alethia. Just with the tafamidis recent results, can you give a bit more color on how you think that impacts the market opportunity for patisiran in hereditary TTR patients who don't have neuro symptoms? So just can you give more details on what your strategy to compete in this segment will be?

Yes, great. Thanks, Ellie. You handle that, Barry?

So, Ellie, as we talked about on the call, the biggest issue we face with hereditary ATTR amyloidosis, and that's a global way, is getting patients found and appropriately diagnosed. As I mentioned, the patient journey can be extremely long with many patients reporting taking 2 years and some over a decade to get properly diagnosed. So we believe that, in general, with more voice out there educating cardiologists, neurologists, neuromuscular specialists, gastroenterologists, to look for the red flag symptoms of the disease and get diagnosis earlier, that the market growth, the number of patients can be significant. So we're looking forward to seeing all the data for all the products out there, including tafamidis, we don't the data yet. And again, we believe that multiple voices will significantly increase the pool. Now as we think about the various products, we're incredibly secure in the product profile we have with patisiran both in terms of efficacy and safety. And as mentioned on the call, believe that it's the most attractive profile and option for patients.

I'll just add one thing, Ellie, obviously, the patients -- we'll have to see how the data come out with tafamidis, we look forward to that in August. But patients will, if we look at the historical tafamidis data where you see a slowing of disease progression, patients will have a choice to either have a drug like patisiran, which is well tolerated and shows a significant improvement in disease in a majority of patients versus a drug that slows things down a little bit. So that's the type of trade-off that will be out there for patients, and we think that will be relevant for all segments of the hereditary ATTR population. Of course, we don't have data to support the wild-type setting and that clearly is an area where tafamidis might be useful until we have data with our TTRsc02 program, which we're also advancing into the wild-type setting. So I hope that answers your question.

And our next question comes from the line of Terence Flynn with Goldman Sachs.

Maybe just wondering if you guys are still confident you'll be able to secure a broad label for patisiran that would allow you to treat a range of hATTR patients? And then on Slide 8, you show this composite of hospitalization and mortality. So when we see the tafamidis data later this year, do you think we're going to be able to compare across these studies? Or are there any other important differences as we think about kind of comparing and contrasting these different data sets?

Thanks, Terence. Let me just touch on the first one and then Akshay should as well, and then we can go to the second question. Look, we believe that the totality of the APOLLO data for patisiran demonstrate an effective patisiran across the entirety of hATTR disease manifestations, and the data are very strong across primary endpoints, secondary endpoints, exploratory endpoints and our submission to the FDA has been around a broad indication, and we believe the science and the data support that. Now there's always a review process and so we will always have that discussion with the FDA, but we believe and still feel confident around our data set that supports a broad label. So Akshay, anything to add to that?

I mean, I agree with that. And I just think for sheer consistency of endpoints that with we -- the outcomes of the endpoints that we have both across neuropathy aspects, cardiomyopathy aspects as well as quality of life, activities of daily living, body mass and the autonomic features, including diarrhea, everything was in favor of the drug. And so that's obviously very encouraging and bodes for potential improvement in patients with a wide spectrum of disease.

With respect to the recent release of the post-hoc analysis, looking at all-cause hospitalization and mortality overall and also than in the cardiac hospitalization setting, these data, obviously, with the caveat of them being post-hoc are nevertheless rather encouraging. You know, 45%, 50% reductions in the event rate across the 2 analysis relative to placebo, and I think quite consistent with the overall pictures I just outlined in terms of all the other numerous endpoints that favors the drug.

As to comparing to any tafamidis data later in the year, these are separate studies, and of course, we have to be cautious when comparing 2 separate studies -- the study populations were different -- this is an hATTR amyloidosis population that has neuropathy and cardiomyopathy. The tafamidis study is in a population that's been defined as having TTR cardiomyopathy, both mutant and wild-type. And so I think we'll have to look at the data in more detail before we attempt to analyze what are the 2 data set teaching us and which patients are most appropriate to get this drug.

Yes. And the only other thing I'd add, Terence, in terms of looking at, is remember, the clinical studies are what they are. The clinical study data we'll see for tafamidis, when we see it in August, was a longer study. So it's hard to compare endpoints -- time points as well.

And our next question comes from the line of Ed Tenthoff with Piper Jaffray.

So excellent update, I really appreciate the details you guys are providing, and congrats on lumasiran. I wanted to get a sense for that market opportunity, obviously we have been focused on sort of some of the other assets and near-term milestones. So I want to get a sense of really how big that market opportunity was? That one sort of snuck up on me a little bit.

Yes. Let me start, and Barry and perhaps Yvonne can jump in as well, if I left something unturned. I'll start by just really emphasizing the enormous disease burden in this setting. Obviously, it typically presents within the pediatric setting. So these are children. In fact, the patients in our Phase I/II study, we have kids as young as 6 years of age. They develop these kidney stones, recurrent kidney damage, they can develop broader systemic effects, including cardiac manifestations. It is ultimately a fatal disease for many patients with really only a double liver-kidney transplant as the only available treatment option for them.

So just a disease of enormous burden. The epidemiology data will indicate that there are a few thousand patients in U.S. and Europe that are out there, but there are also likely patients that are -- have more milder forms of the disease that are not currently diagnosed as having mutations in the gene that is responsible for primary hyperoxaluria. Of interest, there was a recent science paper that highlighted in a [TIVA] study, the identification of a significant number of patients with the disease mutation who, prior to that, had not been diagnosed. So again, a few thousand patients, probably some level of under-diagnosis, maybe not as much as we see with hATTR, but a few thousand patients in the U.S. and Europe. I don't know, if Barry and...

Yes, I guess, to add to -- just to emphasize what John said, very, very sick kids find their way to pediatric nephrologist and get diagnosed. And we see an opportunity, obviously, to intervene earlier in diagnosis and maybe prevent kids from going on dialysis or those who are already on dialysis, lowering the burden of dialysis, which is, as we talked about, 6 days a week, probably need 7, but 6 days a week, to give moms a break. But as John mentioned, what we're also going to be exploring are those that have PH1 but developed kidney stones a little bit later in life. It could be in their teens or their early 20s, that still live with significant risk due to the disease and understanding that patient population is something we're embarking on. Now that could broaden out the number of potential patients as well.

Yvonne, anything else to add? No, you're set. Good. Ted, hopefully, that helps.

And I just had to comment, I think, back to the IPO and 14 years of progress. And it's really great to see you guys delivering here on the promise of RNAi. So keep up the good work and looking forward to the patisiran launch.

Thank you, Ted.

And our next question comes from the line of Gena Wang with Barclays.

Maybe just to follow Terence's question. Wondering, have you submitted new data for all-cause hospitalization and mortality to the FDA? And do you expect these data to be included in the label?

I think I can quickly handle it. These are data that are in the NDA submission, and we would not expect these type of data in the label. It's a post-hoc analysis, Gena. So we would not. But certainly, these data are in the NDA and these are data that we certainly aim to publish in the future. Anything to add to that?

None. I agree, agree.

And then just quickly, do you have any change on the pricing strategy giving tafamidis data?

Barry, you want to handle that?

No. We have the same strategy we've articulated before. We believe that patisiran is offering extremely high value for this rare debilitating, often fatal disease with the reversal of disease manifestations in the majority of patients and are going about it that way. Yes, we're also, as we've articulated, working with payers to make sure that the right kind of agreements are put in place so that access is not an issue, and that's going incredibly well.

Okay. And last, just quickly on lumasiran, what is the European feedback on registration trial? Is it possible to also have a biomarker as a primary endpoint?

Yes. Akshay, you want to handle it?

Yes. We have that work ongoing, but we're confident because of the body of work that already exist in literature that urinary oxalate represents biomarkers that can support approval. So work is ongoing, but we're confident.

And we will certainly engage the EMA. We have PRIME designation, as you know, Gena, we'll engage the EMA on the study design features that we've discussed with the FDA. But feel pretty good about how we'll move forward there.

And our next question comes from the line of Anupam Rama with JPMorgan.

It's Eric in for Anupam. I just wanted to follow up on your comments about the potential breadth of hereditary ATTR label with patisiran. And just wondering whether they similarly apply to CHMP as well as FDA, are there sort of any differences in the conversations that you're having around label breadth between the different agencies? And secondly, it sounds like from their recent earnings call that Pfizer is also looking to reengage or repursue tafamidis in the U.S. for polyneuropathy. I'm just wondering, based on what you're hearing from physicians, whether you anticipate tafamidis either through off-label use or clinical development being sort of a hurdle to commercial uptake and in predominantly polyneuropathy patients, do you kind of see a window with which you kind of have to kind of execute on to establish patisiran as a standard of care in the population?

Yes. Let me tackle the questions, and then Akshay and Barry could jump in, Yvonne as well. The first question on EMA. Well, firstly, we're not, Eric, going to go into details about our discussions, which are confidential with regulators and we're dealing with a competitive landscape as well, so we're going to be protective around that. But we have -- we do believe the data from patisiran and APOLLO support the broad label, and we believe that, that broad label supported both in the U.S. and in Europe. So we've kept consistent with that. And -- but these are discussions that are still ongoing with regulators, and ultimately we'll see where the labels end up. But we do believe the data support the breadth of impact across the entirety of hereditary ATTR. So that's the answer to your question there.

Regarding your second question. Yes, on tafamidis, we think it's possible that they will -- I mean, if I were them, I would look for a broad label as well, including the neuropathy segment, that is possible that they get that with the FDA. As you know, they were rejected in the U.S. because they didn't hit their primary endpoint, but they were approved in Europe. So I think it's very possible that they get a polyneuropathy on their label. But I think that we know what tafamidis does in that setting and it slows down disease a little bit, and if you go to the 80-milligram dose, you're not going to do better than diflunisal, which is a much better stabilizer than tafamidis, and we know what diflunisal does in that setting. It slows things down a little bit, but people still progress.

So I don't think there's any doubt in the minds of physicians who treat these patients that the stabilizers have really shown a relatively incremental impact on neuropathy progression in these patients. So they may well get the label. That's great. Terrific. But I don't think it will change how physicians look at using an agent like patisiran, which really has a very strong impact compared to an agent like tafamidis or for that matter diflunisal, which really only slows down progression. Akshay, anything to add?

Yes. I would just add that in terms of, again, comparing a cross trial to caution, but some notable things about that relative to tafamidis and its future of efficacy related to V30M. And for tafamidis have impacted non-V30M related disease, there's a wealth of literature that's accumulated that patients seem to progress quite quickly, at least that's how the interpretation of that literature and I think of experts as well. And it has this modest effect when it does have effect, as John outlined. We also don't know of its effect in any great detail in the sort of greater manifestations of the disease when we think about the autonomic features in the gut and all these other things we've demonstrated, the gait speed, many other features. We've shown data on now. So of course, we're glad that patients will have other option and we look forward to seeing tafamidis data. But certainly, our package around APOLLO looks the most superior to date, of all the data that are out there, in terms of the comprehensive effect on both neuropathy and cardiomyopathy and the proportion of patients that have the potential to actually improve from the disease.

And our next question comes from the line of Madhu Kumar with B. Riley.

So I was wondering kind of is the kind of timelines for the APOLLO open-label extension trial ending. And then secondly, when you're thinking about the sc02 study in hATTR amyloidosis, how do you think about the positioning of that relative to the launch of patisiran, and kind of as patients gets found, whether they enroll into the sc02 Phase III as compared to going on to patisiran commercially?

Yes, those are two great questions. Akshay, do you want to handle?

Yes, the open-label extension study is going well as we previously reported at ISA earlier this year, we intend to continue with our commitment to the further study of the drug to fully elucidate the efficacy and safety profile and that cohort will be dosed for up to 5 years.

And with respect to the sc02 program, again, our commitment to this patient community and this disease is to study all the drugs we have and haven't, so we'll move expeditiously with sc02. And we also have to remember that the approval of patisiran will be sequential across various territories. And I'm sure that will offer opportunities for patients to receive the patisiran drug, if it's approved in their territory, or to go on to sc02, if they wish to participate in the clinical trial.

Yes. So maybe just adding to that last point a little bit, Madhu, we're going to be very careful to make sure that we think about how we do clinical studies with TTRsc02 in the context of our patisiran launch. And as you know, there are many countries in Europe, for example, where even with an EU approval, which we expect this year, reimbursement will take time, and therefore those patients might be appropriate to be considered in the clinical study, while the reimbursement process for patisiran is being reviewed by governments. So there will be a thoughtful process to make sure that we don't, if you will, cannibalize the initial growth of patisiran by the conduct of TTRsc02 clinical studies.

And then kind of following on the hereditary ATTR trials of sc02. How long do you think you have to treat to show kind of durable TTR knockdown in the Phase III trial?

I could sufficiently point to the Phase I study and say a single dose will be sufficient to show a durable knockdown. I think from the viewpoint of regulators and the entire community, we'd want to show multiple dose exposure in the context of Phase III. And as we guided, Madhu, once every 3 months is not out of the question with the kind of potency and durability we see. So I think we'll have a multi-dose approach, dosing likely once every 3 months.

And our next question comes from the line of Vincent Chen with Bernstein.

One on the TTRsc02 development approach. You mentioned that the development approach for TTRsc02 in wild-type will depend a bit on what the data looks like for tafamidis, the ATTR-ACT Study, in August. Could you provide a little bit more color on what you'll be looking for in the tafamidis data to determine the right approach? What are the ranges of designs or approaches that you'll consider? Would the endpoints change, would the arms change, would the timing -- duration change? And what sort of tafamidis results would potentially tilt you toward one trial design or another?

Well, I mean, just real briefly, I mean, obviously, we're speculating a little bit here, Vincent, and Akshay should comment as well. If the tafamidis data are very modest and largely driven by changes in CD hospitalization and the changes are relatively small, we might still consider doing a placebo-controlled study. I mean, I think that's one option. I don't think we expect that. If, in turn, the results are a little bit more robust and they're seeing an impact on -- in the 20% to 30% range on CD hospitalization and mortality, we would likely go to a head-to-head comparator study where we'd want to demonstrate the superiority of TTRsc02 against tafamidis, so we feel very strong and good about that potential given all the data we have. So those are sort of the 2 bookends from my perspective. I don't know, Akshay, anything to add?

I agree with you, John. Those are the main issues, yes.

And is it fair to say that you would probably need to do a similar endpoint for the all-cause mortality and cardiovascular hospitalizations? Or is it still worth to go with something...

No, no. We were -- our previous plans before the tafamidis top line was that we would need to do a CD hospitalization mortality study endpoint in that setting.

And our next question comes from the line of Maury Raycroft with Jefferies.

Just to follow up on the earlier questions. For patisiran, do you plan on doing and would it be possible to do a 30-month comparison between the APOLLO data and natural history data, looking specifically at survival or cardiac outcomes? And for the outcomes data that you have, do you plan on publishing these data for reference?

Yes. I mean, that's certainly something that we'll be following up on. It's just the natural of course of things and some of the preliminary post-hoc analysis that we presented here, we look forward to validating with outcomes from the early study and compare it to historic control as you say. Now as to whether that would lead to potential label changes, the reimbursement environment setting and what -- how that will be interpreted there, we'll have to see. But I think if tafamidis gets approved and with the prospect of the design study, where the primary endpoint incorporated hospitalization and mortality, I think, those kinds of analysis in comparison to historic controls wouldn't be seen necessarily as sufficient from a regulatory perspective, although we will certainly be publishing those kinds of findings. And I'm confident based on the preliminary post-hoc analysis that we will have encouraging data there.

Got it. Very helpful. And when considering some of the positive cardiac data you've reported for patisiran, do you have any perspective on how regulators will weigh data from the different measures and biomarkers that you're looking at?

Akshay.

Yes. I mean, I think we have provided data both on BMP, which is an important biomarker. That's been associated with adverse outcomes in cardiac amyloidosis, both TTR and AL amyloidosis. We think the literature to support that, experts support that, so we that's an important biomarker to include in a potential label, similarly left ventricular strain. And then finally, the left ventricular thickness data, the structural changes that we're seeing are quite striking. And I think if a prescriber is to know what potential benefits the patient may have, we would want that to be incorporated to show that, by interim, that would suggest that these has to be mobilized from the heart. And finally, all of that added up to an association with an increase in walk speed relative to placebo. And so that was one of the prespecified endpoints, of course, so we expect that to be incorporated in the label. So that's how we're looking at it.

And our next question comes from the line of Alan Carr with Needham & Company.

A couple of them. One, you spent -- you mentioned a few times about the need to find more of these hATTR patients. Maybe in light of the progress that you made with the Alnylam Act program, can you give us a sense of how many diagnosed patients you think there are out there in relation to the total prevalence estimate? And then also with lumasiran, the Phase III program -- or design that you announced earlier, is that a single arm trial, where you're just tracking a change from baseline, or are you going to have a comparator in that?

Yes, great. Well, let's -- I mean, the first question, Barry, why don't you handle that?

Yes. So Alan, as you know, to help out answering that question, since there aren't specific numbers, we would put what we believe are the right kind of diagnosis range based upon what we're hearing versus the epidemiology. And as a demonstration, even in endemic areas like Portugal and Japan, we believe the diagnosis rate once a patient hits a system is only about 50%, and we know many areas the diagnosis rate can be as low as 20%. So -- and that doesn't even acknowledge the time frame difference that it takes. I've already mentioned that most patients report that it's taken over 2 years to get appropriate diagnosis and some over a decade. So as we increase diagnosis rate and shorten the patient journey, and the end should greatly grow over a period of time, and that's the effort just to get out and educate. Because often patients will report that they've seen 2 or 3 gastroenterologists, 2 cardiologists, 2 neurologists, and then finally somebody figures out what's going on after all those medical visits. So the opportunity to educate, raise disease awareness, shorten the patient journey and improve diagnosis is enormous here.

And Yvonne, do you want to comment a little bit on the lumasiran program design and those elements there?

Yes, of course, so it will be a placebo-controlled study. And we'll be kicking that study off shortly as we described in our goals. And we're very confident of the outcome given the endpoints of oxalate learning. So we're pretty excited to get that started and looking forward to the data in due course.

And just one other thing to add there is we've only presented the first cohort's worth data back in November at the ASN meeting, and we'll present -- we now have 20 patients in the Phase I/II study, which we'll present later in the year. And we're obviously very enthusiastic, as is the FDA and EMA about those data, so we look forward to presenting those data later on.

So 25 total divided across 2 arms?

Yes. And obviously, it will be an even number.

And our next question comes from the line of Irina Margine with Cowen.

I just wanted to quickly follow-up on the label questions, and then I have another quick one on givosiran. In your view, what would constitute a broad label? Would it specifically have to mention cardiomyopathy symptoms or just simply not be restricted to patients with pure neuropathy? And how do you expect payers to act in each of these scenarios?

Yes. Let me start and then maybe Akshay can go in. I mean, at 1 -- well, there's always bookends, right? At 1 book end, a broad label would have an indication statement that says patisiran is indicated for the treatment of hereditary ATTR amyloidosis, period. And would have a lot of the cardiac data within the label. At another bookend, it would say neuropathy and it wouldn't have any of the cardiac data in the label. Those are the 2 bookends. We don't expect that last bookend. We do believe that the indication statement is supported by the data and, obviously, we're talking to regulators in the U.S. and EU to support that. And we look forward to announcing it when we have that label, but we believe the data are certainly there to support it. Anything to add?

No, I agree.

Great. And then on givosiran, what will be the pricing strategy given that the initial data will only include the AHA biomarker levels and very preliminary attack rate data? And based on your conversations so far with payers, do you expect they will be willing to cover patients who only have 1 or 2 attacks per year versus more than 3 or 4? And that's...

Yes. Those are great questions. Akshay or Barry, sorry, do you want to handle that?

So we're in preliminary discussions with folks about the disease burden, and keep in mind that the artifact of the clinical trial for 2 or more attacks in 6 months is to get an end to show a difference. We have to power the trial certainly. But you can imagine that the patient is hospitalized once a year, but that hospitalization is for 12 days or those living in significant chronic pain were debilitated, unable to work are also very sick patients. And at the end of the day, payers understand that. And in the United States, we don't think that the limited initial data will be problematic. And keep in mind, we already have, as Akshay commented on the call, pretty profound attack data already. So we'll be able to talk to the full set of data. And as we mentioned, in Europe, we'll wait for the full trial, because that is an instance where in most countries, you go through the health technology assessment process once and have to get it right. So that's one where we want full body of data before negotiating access.

I would just add to what Barry said. There have been at least 2 independent tests of the hypotheses that givosiran causes clinical attacks. There was the initial placebo-controlled element of the Phase I study and then the placebo-patient and that, of course, there's a very impressive reduction of attack rate. Subsequent to that, the placebo patients were rolled over onto active drug and once again, they showed a reduction in attack rate where placebo failed. And so that's rather compelling. And all of those data as well as the long-term open label extension data, some of which we released earlier this year at the EASL meeting, all of that will be in the label and I think very compelling in addition to relationship we've shown between ALA and attack rates. And that would compel, I think, most people to reimburse the drug and help patients with the drug.

And just one more thing to add, I mean, this is a disease with just enormous burden with patients that I mean, sadly, their lives are just completely destroyed by this disease, ravaged by the disease. And so the impact of givosiran is quite clear and ALA is a biomarker that is very predictive of clinical benefits. So that's very helpful.

And our next question comes from the line of David Lebowitz with Morgan Stanley.

Out of curiosity, at the interim analysis, I know that ALA reduction -- sufficient ALA reduction was generally spoken about as being able to lead to an eventual submission. Are there any other efficacy requirements beyond that, that need to be met to enable a submission?

I mean, the simple answer is no. But obviously, the FDA is going to look at the entirety of the package and they're going to look at -- they're not going to see any attack rate data. We agreed to them that. But they'll see safety data. And they'll see attack rate data from the other studies that are ongoing, of course, as well. But you've already seen quite a bit of those data and they look very, very encouraging. So yes, I think, of course, as always with something like this, there's a discussion with the FDA after we get the top line results. But I think we're encouraged by the discussions we've had up until this point, where they understand the enormous disease burden and the importance of getting a new medicine out as quickly as possible.

And one more question. With respect to the cardio population, you spoke about the Alnylam Act effort to diagnose patients. I apologize if I missed this, but how many patients have been identified to this point with Alnylam Act, but also prior to?

Sorry, on porphyria or hATTR?

hATTR.

So I think the numbers are, on top of my head, what we've said 4,600 samples since inception and there have been over 350 patients with TTR mutations that have been detected. That's just in that program. And keep in mind, David, that, that is still just the tip of the iceberg of numbers of physicians that are using the program and it's not being used in Europe, for example. So it's really just a small sample. And then, of course, there are many, many more patients that were already diagnosed outside of that region in the testing program.

Do you have any estimate on patients diagnosed before the program in the U.S?

I mean, certainly, our belief is that there are at least a few thousand patients in the U.S. that are in the system that are diagnosed.

And that's all the time we have today for question and answers. So with that, I'd like to turn the call back over to management for any closing remarks.

Good. Well, thanks, everybody. Obviously, it's an exciting time at the company. We're on the cusp of launching patisiran, and we can't wait to get the approval, get the label and get out and bring this medicine to patients who need it. Thank you very much.

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program, and you may all disconnect. Everyone, have a wonderful day.